Fluoroquinolones
Mark S. Johnson, Pharm.D., BCPS
Associate Professor and Director of
Postgraduate Education
Fluoroquinolones
• Very popular class of antibiotics due to spectrum of
coverage (gram positive, gram negative, atypicals),
unique mechanism of action resulting in inhibition of
bacterial DNA gyrase and topoisomerase IV, excellent
PO bioavailability, fairly well tolerated
– Has led to overprescribing, resistance
• Nalidixic acid was first quinolone (1962)
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Had limited antibacterial activity
Associated with rapid development of bacterial resistance
Was only useful for lower UTI’s
Synthesis led to the evolution of the fluoroquinolones.
Fluoroquinolones
1st generation
2nd generation
3rd generation
Cinoxacin (Cinobac)
Ciprofloxacin (Cipro)
Levofloxacin (Levaquin)
Nalidixic Acid (NegGram)
Ofloxacin (Floxin)
Sparfloxacin (Zagam)
Lomefloxacin (Maxaquin)
Trovafloxacin (Trovan)
Norfloxacin (Noroxin)
Gemifloxacin (Factive)
Gatifloxacin (Tequin)
Moxifloxacin (Avelox)
Increased gram positive coverage with each generation
Nalidixic Acid
http://www.rxlist.com/neggram-drug.htm
Fluoroquinolones
• Mechanism of action
– Block bacterial DNA synthesis by inhibiting bacterial
topoisomerase II (DNA gyrase) and topoisomerase IV
• Inhibition of DNA gyrase prevents the relaxation of
positively supercoiled DNA that is required for normal
transcription and replication
• Inhibition of topoisomerase IV interferes with
separation of replicated chromosomal DNA into the
respective daughter cells during cell division
– Bactericidal
Quinolones
Mechanism of Action
Fluoroquinolones
Spectrum of Activity
• Gram (–) bacilli – Enterobacteriaceae (E. coli,
Salmonella, Shigella, Enterobacter, Klebsiella, Proteus,
Serratia); Campylobacter (increasing resistance);
Pseudomonas aeruginosa (ciprofloxacin, levofloxacin)
• Gram (–) cocci – Neisseria meningitidis
• Gram (+) cocci – Staphylococci (MSSA/MRSA) –
marginal-to-good activity (resistance can form)
– Streptococci (S. pneumoniae) – 3rd generations
• Intracellular/atypical bacterial – Chlamydia;
Mycoplasma; Legionella; Brucella; Mycobacterium
• Anaerobic activity –moxifloxacin
Fluoroquinolones
Resistance
• Resistance mediated by
– Mutations in DNA gyrase
– Change in outer bacterial membrane permeability
– Variant of an aminoglycoside acetyltransferase
Fluoroquinolones
PKS
• Absorption
– Excellent BA (80-95%)
• Distribution
– Widely distributed in body fluids and tissues
• Elimination
– Mainly by renal tubular secretion or glomerular filtration
– Moxifloxacin—hepatic metabolism, some urinary excretion
– Gemifloxacin—both renal and hepatic
Fluoroquinolones
Some Clinical Uses
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Urinary Tract Infections (not Moxifloxacin)
Respiratory Tract Infections
GI Infections
Soft tissues, bones, joints
Intra-abdominal infections
Anthrax
Others
Fluoroquinolones
ADR’s
• GI—nausea, vomiting, diarrhea
• CNS – headache, dizziness, sleep disturbances, and confusion
• QT prolongation
• sparfloxacin >grepafloxacin > moxifloxacin > gatifloxacin >
levofloxacin > ciprofloxacin > ofloxacin
• Tendonitis, tendon rupture
• Joint cartilage damage/arthropathy--<18yo
• Photosensitivity
• Hepatotoxity (moxifloxacin)
• Hyper/hypoglycemia
• Clostridium difficile diarrhea
• Skin rash (gemifloxacin)
Fluoroquinolones
Drug Interactions
• Drug interactions:
– Quinolones’ absorption reduced by: di-, tri-valent cations
(antacids, Ca supplements, iron, MVI, diary products, etc),
sucralfate, ddi
– Space out as far apart as can (at least 2h, but more better)
– Quinolones can inhibit metabolism of: theophylline,
caffeine, warfarin
Fluoroquinolones
2nd generation
• Ciprofloxacin (Cipro, Cipro XR, Proquin XR)
• Coverage: pseudomonas coverage, good gram – coverage
(E. coli, salmonella, Shigella, Neirsseria, Legionella), some
gram + ( no strep pneumo), Atypical coverage
– Good for UTIs, pyelonephritis, prostatitis, osteomyelitis,
anthrax, infectious diarrhea, travelers diarrhea, typhoid
fever, intra-abdominal infections (with metronidazole),
possible RTI’s, possible skin
– Dosing:
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PO 250-500-750mg BID
XR 500-1000mg QD
IV 400mg Q8-12h
Ophthalmic solution 0.3%
Fluoroquinolones
2nd generation
• Ofloxacin (Floxin)
• Coverage similar to ciprofloxacin (except
Pseudomonas)
• Used for: primarily for UTI’s and nongonococcal
urethritis and cervicitis
• Dosing
• 200-400mg PO BID
• Ophthalmic Solution 0.3% (Ocuflox)
Fluoroquinolones
2nd generation
• Norfloxacin (Noroxin)
• Used for UTI’s, prostatitis
• Dosing:
• PO 400mg BID
Fluoroquinolones
3rd Generation
• Levofloxaxin (Levaquin)
– L-isomer of ofloxacin
– Improved Gram + coverage and similar Gram –,
some Pseudomonas coverage
– Used for CAP, COPD exacerbations, sinusitis,
skin infections, complicated UTIs
• “Respiratory fluoroquinolone”
– Dosing:
• 250mg-750mg PO/IV Q24h
• Ophthalmic solution (Iquix 1.5%, Quixin 0.5%)
Fluoroquinolones
3rd Generation
• Moxifloxacin (Avelox)
– No renal adjustment, no urinary penetration
– Gram negative and positive coverage (high
activity for Streptococcus pneumoniae
(MDRSP), anaerobes
– Uses: pneumonia, AECB, sinusitis, intraabdominal infections, skin/skin structure
• “Respiratory Fluoroquinolone”
– Dosing:
• 400mg IV/PO Q24h
• Ophthalmic 0.5% (Vigamox)
Fluoroquinolones
3rd Generation
• Gemifloxacin (Factive)
– Similar in coverage to other 3rd generation FQ
(not pseudomonas, not anaerobes)
– Uses: pneumonia, AECB
• “Respiratory fluoroquinolone”
– ADR’s: Rash (incidence higher in females, >5d
therapy, < 40yo)
– Dosing:
• 320 PO Q24h